The present invention relates to novel aminomethylene substituted non-aromatic heterocycles, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of inflammatory and central nervous system disorders, as well as several other disorders. The pharmaceutically active compounds of this invention are substance P receptor antagonists. This invention also relates to novel intermediates used in the synthesis of such substance P receptor antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283.
The following references refer, collectively, to quinuclidine, piperidine, and azanorbornane derivatives and related compounds that exhibit activity as substance P receptor antagonists: U.S. Pat. No. 5,162,339, which issued on Nov. 11, 1992; U.S. patent application No. 724,268, filed Jul. 1, 1991; PCT Patent application PCT/US 91/02853, filed Apr. 25, 1991; PCT Patent application PCT/US 91/03369, filed May 14, 1991; PCT Patent application PCT/US 91/05776, filed Aug. 20, 1991; PCT Patent application PCT/US 92/00113, filed Jan. 17, 1992; PCT Patent application PCT/US 92/03571, filed May 5, 1992; PCT Patent application PCT/US 92/03317, filed Apr. 28, 1992; PCT Patent application PCT/US 92/04697, filed Jun. 11, 1992; U.S. patent application 766,488, filed Sep. 26, 1991; U.S. patent application 790,934, filed Nov. 12, 1991; PCT Patent application PCT/US 92/04002, filed May 19, 1992; Japanese Patent Application 065337/92, filed Mar. 23, 1992; and U.S. patent application 932,392, filed Aug. 19, 1992.
The present invention relates to compounds of the formula 
wherein A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the side chain containing NR2R3 is attached to a carbon atom of ring system A;
W is hydrogen, (C1-C6)alkyl optionally substituted with from one to three fluorine atoms, xe2x80x94S(O)v-(C1-C6)alkyl wherein v is zero, one or two, halo, benzyloxy or (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms;
R1 is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-tirazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazolyl or thiophenyl), wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C1-C6) alkyl optionally substituted with from one to three fluorine atoms and (C1-C6)alkoxy optionally substituted with from one to three fluorine atoms;
the dotted lines in formula Ib indicate that one of the Xxe2x80x2-Yxe2x80x2 and Yxe2x80x2-Zxe2x80x2 bonds may optionally be a double bond;
Xxe2x80x2 is selected from xe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R4)-, xe2x80x94NHxe2x80x94, xe2x95x90Nxe2x80x94, xe2x80x94CH[(C1-C6)alkyl]-, xe2x95x90C[(C1-C6)alkyl]-, xe2x80x94CH(C6H5)- and xe2x95x90C(C6H5)-;
Yxe2x80x2 is selected from Cxe2x95x90O, Cxe2x95x90NR4, Cxe2x95x90S, xe2x95x90CHxe2x80x94, xe2x80x94CH2-, xe2x95x90C[(C1-C6)alkyl]-, xe2x80x94CH[(C1-C6)alkyl]-, xe2x95x90C(C6H5)-, xe2x80x94CH(C6H5)-, xe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94N(R4)-, xe2x95x90C(halo)-, xe2x95x90C(OR4)-, xe2x95x90C(SR4)-, xe2x95x90C(NR4)-, xe2x80x94Oxe2x80x94, xe2x95x90C(CF3)-, xe2x95x90C(CH2C6H5)-, xe2x80x94Sxe2x80x94 and SO2, wherein the phenyl moieties of said xe2x95x90C(C6H5)- and xe2x80x94CH(C6H5)- may optionally be substituted with from one to three substituents independently selected from trifluoromethyl and halo, and wherein the alkyl moieties of said xe2x95x90[(C1-C6)alkyl]- and xe2x80x94CH[C1-C6)alkyl]- may optionally be substituted with from one to three fluorine atoms;
Zxe2x80x2 is selected from xe2x95x90CHxe2x80x94, xe2x80x94CH2-, xe2x95x90Nxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R4)-, xe2x95x90C(C6H5)-, xe2x80x94CH(C6H5)-, xe2x95x90C[(C1-C6)alkyl]- and xe2x80x94CH[(C1-C6)alkyl]-;
or Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2, together with the two carbon atoms shared between the benzo ring and the Xxe2x80x2Yxe2x80x2Zxe2x80x2 ring, form a fused pyridine or pyrimidine ring;
R2 is hydrogen or xe2x80x94CO2(C1-C10)alkyl;
R3 is selected from 
wherein R6 and R10 are independently selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C1-C3) alkoxy-carybonyl;
R4 is (C1-C6) alkyl or phenyl;
R7 is selected from (C3-C4) branched alkyl, (C5-C6) branched alkenyl, (C5-C7) cycloalkyl, and the radicals named in the definition of R6;
R8 is hydrogen or (C1-C6) alkyl;
R9 and R19 are independently selected from phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl and furyl, and R9 and R19 may optionally be substituted with from one to three substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms and (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms;
Y is (CH2)l wherein l is an integer from one to three, or Y is a group of the formula 
Z is oxygen, sulfur, amino, (C1-C3)alkylamino or (CH2)n wherein n is zero, one or two;
x is zero, one or two;
y is zero, one or two;
z is three, four or five;
o is two or three;
p is zero or one;
r is one, two or three;
the ring containing (CH2)z may contain from zero to three double bonds, and one of the carbon atoms of (CH2)z may optionally be replaced by oxygen, sulfur or nitrogen;
R11 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms and (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms;
X is (CH2)q wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R14, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R15;
m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m, wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH2)m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m may optionally be substituted with R17;
R12 is a radical selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thizaolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C2-C6) alkyl, benzhydryl and benzyl, wherein the point of attachment on R12 is a carbon atom unless R12 is hydrogen, and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, (C1-C6)-alkylamino, 
and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
R13 is hydrogen, phenyl or (C1-C6)alkyl;
or R12 and R13, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms that is neither the point of attachment of the spiro ring nor adjacent to such point of attachment may optionally be replaced by oxygen, nitrogen or sulfur;
R14 and R15 are each independently selected from hydrogen, hydroxy, halo, amino, oxo (xe2x95x90O), cyano, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, (C1-C6)alkylamino, 
set forth in the definition of R12;
R16 is 
NHCH2R18, SO2R18, CO2H or one of the radicals set forth in any of the definitions of R12, R14 and R15;
R17 is oximino (xe2x95x90NOH) or one of the radicals set forth in any of the definitions of R12, R14 and R15; and
R18 is (C1-C6)alkyl, hydrogen, phenyl or phenyl (C1-C6)alkyl;
with the proviso that (a) when m is 0, one of R16 and R17 is absent and the other is hydrogen, (b) when R3 is a group of the formula VIII, R14 and R15 cannot be attached to the same carbon atom, (c) when R14 and R15 are attached to the same carbon atom, then either each of R14 and R15 is independently selected from hydrogen, fluoro, (C1-C6)alkyl, hydroxy-(C1-C6)alkyl and (C1-C6)alkoxy-(C1-C6)alkyl, or R14 and R15, together with the carbon to which they are attached, form a (C3-C6) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; (d) R12 and R13 can not both be hydrogen, and (e) when R14 or R15 is attached to a carbon atom of X or (CH2)y that is adjacent to the ring nitrogen, then R14 or R15, respectively, must be a substituent wherein the point of attachment is a carbon atom.
The present invention also relates to the pharmaceutically acceptable acid addition and base salts of compounds of the formulae Ia and Ib (hereinafter referred to, collectively, as compounds of the formula I). The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrchloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)]salts. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
The fused bicyclic nucleus of compounds of the formula Ib to which W and the xe2x80x94CH2NR2R3 sidechain are attached may be, but is not limited to one of the following groups: benzoxazolyl, benzthiazolyl, benzimidazolyl, benzisoxazolyl, benzoisothiazolyl, indazolyl, indolyl, isoquinolinyl, benzofuryl, benzothienyl, oxindolyl, benzoxazolinonyl, benzthiazolinonyl, benzimidazolinonyl, benzimidazolniminyl, dihydrobenzothienyl-S,S-dioxide, benztriazolyl, benzthiadiazolyl, benzoxadiazolyl, and quinazolinyl.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, includes O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is defined as above.
The term xe2x80x9cone or more substituents,xe2x80x9d as used herein, includes from one to the maximum number of substituents possible based on the number of available bonding sites.
Preferred compounds of this invention include those compounds of the formula I wherein the substituents at positions xe2x80x9c2xe2x80x9d and xe2x80x9c3xe2x80x9d of the nitrogen containing ring of R3 are in a cis configuration. When R3 is a group of the formula VII or VIII, xe2x80x9ca cis configurationxe2x80x9d, as used herein, means that the non-hydrogen substituent at position xe2x80x9c3xe2x80x9d is cis to R12.
Other preferred compounds of this invention include those compounds of the formula Ia wherein R3 is a group of the formula III, VII or IX; R2 is hydrogen; A is phenyl or indolinyl; W is (C1-C3)alkoxy optionally substituted with from one to five fluorine atoms; and R1 is thiazolyl, imidazolyl, thiadiazolyl, pyrrolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazolyl or thiophenyl, and R1 may optionally be substituted with one or two (C1-C3) alkyl moieties.
Other preferred compounds of this invention include those compounds of the formula Ib wherein R3 is a group of the formula III, VII or IX; R2 is hydrogen; the fused bicyclic ring system to which W and the xe2x80x94CH2NR2R3 sidechain are attached is benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiophenyl or benzimidazolyl; and W is (C1-C6)alkoxy optionally substituted with from one to five fluorine atoms.
More preferred compounds of this invention are the foregoing preferred compounds wherein: (a) R3 is a group of the formula III and R9 is benzhydryl; (b) R3 is a group of the formula VII, R12 is phenyl, each of R13, R14, R15 and R16 is hydrogen, m is zero and X is -(CH2)3-; or (c) R3 is a group of the formula IX, r is two and R19 is benzhydryl.
Other more preferred compounds of this invention are those compounds of the formula Ia wherein: (a) R3 is a group of the formula III wherein the substituents at positions xe2x80x9c2xe2x80x9d and xe2x80x9c3xe2x80x9d of the nitrogen containing ring are in the cis configuration, R9 is benzhydryl and A is phenyl; or (b) R3 is a group of the formula VII wherein R12 and the substituent at position xe2x80x9c3xe2x80x9d of the nitrogen containing ring are in the cis configuration, A is phenyl, R12 is phenyl, each of R2, R13, R14, R15 and R16 is hydrogen, m is zero, W is methoxy or isopropoxy, X is -(CH2)3- and R1 is thiazolyl, imidazolyl, pyrrolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiophenyl or thiadiazolyl.
Other more preferred compounds of this invention are those compounds of the formula Ib wherein R3 is a group of the formula IX wherein the substituents at positions xe2x80x9c2xe2x80x9d and xe2x80x9c3xe2x80x9d of the nitrogen containing ring are in the cis configuration, R19 is benzhydryl, r is two and the fused bicyclic ring system to which W and the xe2x80x94CH2NR2R3 sidechain are attached is benzisoxazolyl or benzthiazolyl.
Especially preferred compounds of the formula Ib are those wherein R3 is a group of the formula IX, R19 is benzhydryl, the fused bicyclic ring system to which W and the xe2x80x94CH2NR2R3 sidechain are attached is benzisoxazolyl, and W is methoxy.
Other especially preferred compounds of the formula Ib are those wherein R3 is a group of the formula VII, R12 is phenyl, each of R13, R14, R15 and R16 is hydrogen, m is zero, X is -(CH2)3-, and the fused bicyclic ring system to which W and the xe2x80x94CH2NR2R3 sidechain are attached is benzothiazolyl, benzoxazolyl, benzthiophenyl or benzimidazolyl.
Especially preferred compounds of the formula Ia are those wherein R3 is a group of the formula VII, each of R13, R14, R15 and R16 is hydrogen, m is zero, X is -(CH2)3-, A is phenyl, W is methoxy, and R1 is selected from thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiophenyl and isoxazolyl.
Specific preferred compounds of the formula I include the following:
(2S,3S)-3-[2-methoxy-5-(2-thiazolyl)benzyl]amino-2-phenylpiperidine;
(2S,3S)-3-[5-(2-imidazolyl)-2-methoxybenzyl]amino-2-phenylpiperidine;
(2S,3S)-3-[2-methoxy-5-(2-oxopyrrolidinyl)benzyl]amino-2-phenylpiperidine;
(2S,3S)-3-[2-methoxy-5-(4-methyl-2-thiazolyl)benzyl]-amino-2-phenylpiperidine;
(2S,3S)-3-[2-methoxy-5-(1,2,3-thiadiazol-4-yl)benzyl]-amino-2-phenylpiperidine;
(2S,3S)-(6-methoxy-2-methyl-benzothiazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)amine;
(2S,3S)-[5-(2,5-dimethyl-pyrrol-1-yl)-2-methoxybenzyl]-(2-phenylpiperidin-3-yl)amine;
(2S,3S)-3-[2-methoxy-5-(5-oxazolyl)benzyl]amino-2-phenylpiperidine;
(2S,3S)-(6-methoxy-2-phenyl-benzothiazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)-amine;
(2S,3S)-(6-methoxy-2-cyclopropyl-benzothiazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)amine;
(2S,3S)-(6-methoxy-2-tert-butyl-benzothiazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)amine;
(2S,3S)-(6-isopropoxyoxy-2-phenyl-benzothiazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)amine;
(2S,3S)-(6-isopropoxyoxy-2-methyl-benzothiazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)amine;
(2S,3S)-(6-trifluoromethoxy-2-methyl-benzothiazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)amine;
(2S,3S)-(6-methoxy-2-methyl-benzoxazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)amine;
(1SR,2SR,3SR,4RS)-3-[6-methoxy-3-methylbenzisoxazol-5-yl]methylamino-2-benzhydrylazanorbornane;
(2S,3S)-(2-methoxy-5-pyridin-2-ylbenzyl)-(2-phenylpiperidin-3-yl)amine;
(2S,3S)-(2-methoxy-5-pyrimidin-2-ylbenzyl)-2-phenylpiperidin-3-yl)amine;
(2S,3S)-(2-methoxy-5-pyridin-3-ylbenzyl)-2-phenylpiperidin-3-yl)amine;
(2S,3S)-[2-methoxy-5-(6-methylpyridin-2-yl)benzyl]-(2-phenylpiperidin-3-yl)amine;
(2S,3S)-[5-(3,5-dimethylpyrazol-1-yl)-2-methoxybenzyl]-(2-phenylpiperidin-3-yl)amine;
(2S, 3S)-[2-methoxy-5-(3,4,5-trimethylpyrazol-1- yl)benzyl]-(2-phenylpiperidin-3-yl)amine;
(2S, 3S)-[2-isopropoxy-5-(3,4,5-trimethylpyrazol-1-yl)benzyl]-(2-phenylpiperidin-3-yl)amine;
(2S, 3S)-[5-(3,5-diisopropylpyrazol-1-yl)-2-methoxybenzyl]-(2-phenylpiperidin-3-yl)amine;
(2S, 3S)-[5-(3,5-dimethylthiophen-2-yl)-2-methoxybenzyl]-(2-phenylpiperidin-3-yl)amine; and
(2S, 3S)-(6-methoxy-2,3-dimethyl-benzo[b]thiophen-7-ylmethyl)-(2-phenylpiperidin-3-yl)amine.
Other compounds of the formula I include the following:
(2S, 3S)-(6-methoxy-3-methyl-benzo-[d]isoxazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)-amine;
(1SR, 2SR, 3SR, 4RS)-(2-benzhydryl-1-aza-bicyclo[2.2.1]hept-3-yl)-(6-methoxy-2-methyl-benzothiazol-5-ylmethyl)-amine;
(2S, 3S)-(6-methoxy-benoxazol-5-ylmethyl)-(2-phenyl-piperidin-3yl)-amine;
(2S, 3S)-(6-methoxy-benzothiazol-5-ylmethyl)-(2-phenyl-piperidin-3-yl)-amine;
(2S, 3S)-5-methoxy-1-methyl-6-(2-phenylpiperidin-3-ylaminomethyl)-1,3-dihydro-indol-2-one;
(2S, 3S)-6-methoxy-3-methyl-5-(2-phenylpiperidin-3-ylaminomethyl)-3H-benzoxazol-2-one;
(2S, 3S)-6-methoxy-3-methyl-5-(2-phenylpiperidin-3-ylaminomethyl)-3H-benzoxazol-2-one;
(2S, 3S)-5-methoxy-1,3-dimethyl-6-(2-phenylpiperidin-3-ylaminoethyl)-1,3-dihydro-benzoimidazol-2-one;
(2S, 3S)-(6-methoxy-3-methyl-3H-benzotriazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)amine;
(2S, 3S)-(2-methoxy-5-[1,2,3]thiadiazol-4-yl-benzyl)-(2-phenyl-1-azabicyclo[2.2.2]oct-3-yl)amine;
(2S, 3S)-(2-methoxy-5-[1,2,3]thiadiazol-4-yl-benzyl)-(2-benzhydryl-1-azabicyclo[2.2.2]oct-3-yl)amine;
(2S, 3S)-(6-methoxy-2-methyl-benzothiazol-5-ylmethyl)-(2-phenyl-1-azabicyclo[2.2.2]oct-3-yl)amine;
(2S, 3S)-6-methoxy-2-methyl-benzothiazol-5-ylmethyl)-(2-benzhydryl-1-azabicyclo[2.2.2]oct-3-yl)amine;
(2S, 3S)-(2-methoxy-5-thiazol-2-yl-benzyl)-(2-benzhydryl-1-azabicyclo[2.2.2]oct-3-yl-benzyl)-(2-benzhydryl-1-azabicyclo[2.2.2]oct-3-yl)amine;
(2S, 3S)-(6-methoxy-2-methyl-benzothiazol-5-ylmethyl)-(2-phenyl-1-azabicyclo[2.2.1]hept-3-yl)amine;
(2S, 3S)-(6-methoxy-2-methyl-benzothiazol-5-ylmethyl)-(2-benzhydryl-1-azabicyclo[2.2.1]hept-3-yl)amine;
(2S, 3S)-(2-methoxy-5-[1,2,4]triazol-4-yl-benzyl)-(2-phenylpiperidin-3-yl)amine;
(2S, 3S)-(2-methoxy-5-[1,2,4]triazol-1-yl-benzyl)-(2-phenylpiperidin-3-yl)amine;
(2S, 3S)-(2-methoxy-5-thiazol-2-ylbenzyl)-(2-phenyl-decahydroquinolin-3-yl)amine;
(2S, 3S)-(2-methoxy-5-thiazol-2-ylbenzyl)-(2-phenyl-octahydro-indol-3-yl)amine;
(2S, 3S)-(2-methoxy-5-oxazol-4-ylbenzyl)-(2-phenylpiperidin-3-yl)amine;
(2S, 3S)-(6-methoxy-2-(2-propyl)-benzothiazol-5-ylmethyl)-(2-phenylpiperidin-3-yl)-amine;
(1SR, 2SR, 3SR, 4RS)-(2-benzhydryl-1-azabicyclo[2.2.1]hept-3-yl)-(6-methoxy-2-phenyl-benzothiazol-5-ylmethyl)amine;
(1SR, 2SR, 3SR, 4RS)-(2-benzhydryl-1-azabicyclo[2.2.1]hept-3-yl)-(6-methoxy-2-cyclopropyl-benzothiazol-5-ylmethyl)amine;
(1SR, 2SR, 3SR, 4RS)-(2-benzyhydryl-1-azabicyclo[2.2.1]hept-3-yl)-(6-methoxy-2-tert-butyl-benzothiazol-5-ylmethyl)amine;
(1SR, 2SR, 3SR, 4RS)-(2-benzhydryl-1-azabicyclo[2.2.1]hept-3-yl)-(6-methoxy-2-(2-propyl)-benzothiazol-5-ylmethyl)amine;
(1SR, 2SR, 3SR, 4RS)-(2-benzhydryl-1-azabicyclo[2.2.1]hept-3-yl)-(6-isopropoxyoxy-2-phenyl-benzothiazol-5-ylmethyl)amine;
(1SR, 2SR, 3SR, 4RS)-(2-benzhydryl-1-azabicyclo[2.2.1]hept-3-yl)-(6-isopropoxyoxy-2-methyl-benzothiazol-5-ylmethyl)amine;
(1SR, 2SR, 3SR, 4RS)-(2-benzhydryl-1-azabicyclo[2.2.1]hept-3-yl)-(6-trifluoromethoxy-2-methyl-benzothiazol-5-ylmethyl)amine;
(6-methoxy-1-oxa-2,3-diazainden-5-ylmethyl)-(2-phenyl-piperidin-3-yl)amine; and
(6-methoxy-2-methyl-1H-benzoimidazol-5-ylmethyl)-(2-phenylpiperidine-3-yl)amine.
The present invention also relates to compounds of the formulae 
wherein ring A, R1, R3, W, Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2 are defined as above. It also relates to compounds of the formula 
wherein Xxe2x80x2 is xe2x80x94Sxe2x80x94 or xe2x80x94Oxe2x80x94, and each Yxe2x80x2 and Zxe2x80x2 is, independently, xe2x95x90Nxe2x80x94, xe2x95x90Cxe2x80x94, xe2x95x90C[(C1-C6)alkyl]xe2x80x94 or xe2x95x90C(C6H5)xe2x80x94, wherein the alkyl moiety of said xe2x95x90C[(C1-C6)alkyl]xe2x80x94 may optionally be substituted with from one to three fluorine atoms and the phenyl moiety of said xe2x95x90C(C6H5)xe2x80x94 may optionally be substituted with from one to three substituents independently selected from halo and trifluoromethyl, with the proviso that Yxe2x80x2 and Zxe2x80x2 can not both be xe2x95x90Nxe2x80x94, and R22 is methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, (C1-C6)alkyl, (C3-C6)cycloalkyl or benzyl. Compounds of the formulae XI, XII, XI-A, XII-A and XVIII are intermediates in the synthesis of compounds of the formulae Ia and Ib. 
The present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, urinary incontinence, gastrointestinal disorders such as emesis and colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasopastic diseases such as angina, migraine and Reynaud""s disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer""s disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in a mammal, including a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, urinary incontinence, gastrointestinal disorders such as emesis and colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasopastic diseases such as angina, migraine and Reynaud""s disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer""s disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such condition.
The present invention also relates to a pharmaceutical composition for antagonizing the effects of substance P in a mammal, including a human, comprising a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of antagonizing the effects of substance P in a mammal, including a human, comprising administering to said mammal a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder in a mammal, including a human, resulting from an excess of substance P, comprising a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or preventing a disorder in a mammal, including a human, resulting from an excess of substance P, comprising administering to said mammal a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.
The present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, urinary incontinence, gastrointestinal disorders such as emesis and colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasopastic diseases such as angina, migraine and Reynaud""s disease, fibrosing and collagen disease such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer""s disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in a mammal, including a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in antagonizing the effect of substance P at its receptor site, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, urinary incontinence, gastrointestinal disorders such as emesis and colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasopastic diseases such as angina, migraine and Reynaud""s disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer""s disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in antagonizing the effect of substance P at its receptor site.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder in a mammal, including a human, the treatment or prevention of which is effected or facilitates by a decrease in substance P mediated neurotransmission, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in antagonizing the effect of substance P at its receptor site, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or preventing a disorder in mammal, including a human, the treatment or prevention of which is effected of facilitated by a decrease in substance P mediated neurotransmission, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in antagonizing the effect of substance P at its receptor site.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder in a mammal, including a human, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or preventing a disorder in mammal, including a human, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder.
The compounds of the formula I have chiral centers and therefore exist in different enantiomeric forms. This invention relates to all optical isomers and all stereoisomers of compounds of the formula I, and mixtures thereof.
The compounds of the formula I may be prepared as described in the following reaction schemes and discussion. Unless otherwise indicated, ring A, W, R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R22, X, Z, Y, Xxe2x80x2, Yxe2x80x2, Zxe2x80x2, m, n, o, p, q, r, x, y, and z, and structural formulas Ia, Ib, II, III, IV, V, VI, VII, VIII, IX, XI, XII, XI-A and XII-A in the reaction schemes and discussion that follow are defined as above.
As indicated above, compounds of the formulae Ia and Ib are referred to, collectively, as xe2x80x9ccompounds of the formula Ixe2x80x9d. 
Scheme 1 illustrates the preparation of compounds of the formula Ia from starting materials of the formula X wherein G is hydrogen, hydroxy, chloro, bromo or (C1-C6)alkoxy.
Referring to scheme 1, a compound of the formula X wherein G is hydrogen may be converted directly into the corresponding compound of the formula I by reacting it with a compound of the formula NH2R3 in the presence of a reducing agent. Reducing agents that may be used include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, hydrogen and a metal catalyst, zinc and hydrochloric acid, and formic acid. This reaction is typically conducted in a reaction inert solvent at a temperature from about 0xc2x0 C. to about 150xc2x0 C. Suitable reaction inert solvents include lower alcohols (e.g., methanol, ethanol and isopropanol), 1,2dichloroethane, acetic acid and tetrahydrofuran (THF). Preferably, the solvent is acetic acid, the temperature is about 25xc2x0 C., the reducing agent is sodium triacetoxyborohydride, and the reaction is conducted in the presence of a dehydrating agent such as molecular sieves.
Alternatively, the reaction of a compound of the formula X with a compound of the formula NH2R3 may be carried out in the presence of a dehydrating agent or by using an apparatus designed to remove azeotropically the water generated, to produce an imine of the formula 
which is then reacted with a reducing agent as described above, preferably with sodium triacetoxyborohydride in an acetic acid or 1,2-dichloroethane solvent at about room temperature. The preparation of the imine XI is generally carried out in a reaction inert solvent such as benzene, xylene or toluene, preferably toluene, at a temperature from about 25xc2x0 C. to about 110xc2x0 C., preferably at about the reflux temperature of the solvent. Suitable dehydrating agents/solvent systems include titanium tetrachloride/dichloromethane, titanium isopropoxide/dichloromethane and molecular sieves. Titanium tetrachloride/dichloromethane is preferred.
Compounds of the formula X wherein G is hydroxy, chloro, bromo or (C1-C6)alkoxy may be converted into the corresponding compounds of formula XII having the desired R3 group by reacting them with the appropriate compound of the formula NH2R3 under conditions that will be obvious to those skilled in the art, and then reducing the resulting amides to yield the desired compounds having formula I wherein R2 is hydrogen. When G is hydroxy, the compound of formula X is reacted with NH2R3 in the presence of an activating agent. Appropriate activating agents include carbonyldiimidazole, chloroformates such as isobutyl chloroformate, diethylphosphoryl cyanide and dicyclohexylcarbodiimide. Carbonyldiimidazole is preferred. This reaction is generally conducted at a temperature from about 0xc2x0 C. to about 50xc2x0 C., preferably at about 25xc2x0 C., in an inert solvent such as chloroform, dimethyl ether, THF or dimethyformamide (DMF).
When G is chloro or bromo, the reaction of the compound of formula X with the appropriate compound of formula NH2R3 is typically carried out in the presence of an acid scavenger in an aprotic solvent at a temperature from about 0xc2x0 C. to about 100xc2x0 C. Suitable acid scavengers include triethylamine (TEA), pyridine and inorganic salts such as sodium and potassium carbonate. Suitable solvents include methylene chloride (CH2Cl2), chloroform (CHCl3), benzene, toluene and tetrahydrofuran (THF). Preferably, the reaction is conducted in CH2Cl2 at room temperature using TEA as the acid scavenger.
When G is Oxe2x80x94(C1-C6)alkyl, the reaction of the compound of formula NH2R3 is usually conducted in an aprotic solvent such as benzene, toluene, chlorobenzene or xylenes, at a temperature from about 25xc2x0 C. to about 100xc2x0 C., preferably at about the reflux temperature of the solvent.
Reduction of the compound of formula XII so formed yields the corresponding compound of the formula I wherein R2 is hydrogen. This is generally accomplished using a reducing agent such as lithium aluminum hydride, borane dimethylsulfide complex, borane-THF or diborane, in an aprotic solvent such as THF, dioxane or diethyl ether, at a temperature from about 0xc2x0 C. to about 70xc2x0 C. Preferably, the reducing agent is borane dimethylsulfide complex and the reaction is carried out at room temperature in an ethereal solvent such as THF.
Compounds of the formula Ib may also be prepared by the procedures depicted in schemes 1 and 2 and described above, with the exception that ring system A in intermediate compounds X, XI and XII is replaced with the fused bicyclic ring system of the desired compound of formula Ib and R1 is absent.
Compounds of the formula I wherein R2 is hydrogen may be converted into the corresponding compounds wherein R2 is xe2x80x94CO2(C1-C10)alkyl by reacting them with a (C1-C10)alkyl halocarbonate such as methyl or ethyl chloroformate in the presence of an acid scavenger. Typically, this reaction is conducted in an polar solvent such as chloroform, methylene chloride, water or a water/acetone mixture, at a temperature from about 0xc2x0 C. to about 100xc2x0 C., preferably at about room temperature. Suitable acid scavengers include triethylamine, pyridine and potassium and sodium carbonate or bicarbonate.
When R3 is a group of the formula II, the starting materials of the formula NH2R3 may be prepared as described in U.S. Pat. No. 5,162,339, which issued on Nov. 11, 1992. This patent is incorporated herein in its entirety.
When R3 is a group of the formula III, the starting materials of the formula NH2R3 may be prepared as described in U.S. patent application Ser. No. 07/532,525, filed Jun. 1 1990 and PCT patent application PCT/US 91/02853, filed Apr. 25, 1991. Both these applications are incorporated herein in their entirety.
When R3 is a group of the formula IV, V or VI, the starting materials of the formula NH2R3 may be prepared as described in U.S. patent application Ser. No. 07/552,442, filed Jul. 23, 1990 and PCT patent application PCT/US 91/03369, filed May 14, 1991. Both these applications are incorporated herein in their entirety.
When R3 is a group of the formula VII, the starting materials of the formula NH2R3 may be prepared as described in U.S. patent application Ser. No. 07/724,268, filed Jul. 1, 1991, U.S. patent application Ser. No. 07/800,667, filed Nov. 27, 1991 and PCT patent application PCT/US 92/00065, filed Jan. 14, 1992. These applications are incorporated herein in their entirety.
When R3 is a group of the formula VIII, the starting materials of the formula NH2R3 may be prepared as described in PCT patent application PCT/US 91/05776, filed Aug. 20, 1991, U.S. patent application Ser. No. 07/800,667, filed Nov. 27, 1991 and PCT patent application PCT/US 92/00065, filed Jan. 14, 1992. These applications are incorporated herein in their entirety.
When R3 is a group of the formula IX, the starting materials of the formula NH2R3 may be prepared as described in U.S. patent application Ser. No. 07/719,884, filed Jun. 21, 1991. This application is incorporated herein in its entirety.
Scheme 2 illustrates one method of preparing the starting materials of formula X wherein G is hydrogen. This is preferred method of preparing compounds of the formula X wherein G is hydrogen and R1 is thiazolyl, thiadiazolyl and oxazolyl. Once formed, these compounds can be converted to the corresponding compounds of the formula I or XI according to the procedures described above.
Referring to scheme 2, a compound of the formula XIII is reacted with titanium tetrachloride (TiCl4) or tin tetrachloride (SnCl4) and dichloromethyl methyl ether (CHCl2xe2x80x94Oxe2x80x94CH3) at a temperature from about 0xc2x0 C. to about room temperature, preferably at about 0xc2x0 C., in a methylene chloride or tetrachloroethylene solvent to yield the corresponding aldehyde of formula X wherein G is hydrogen. Alternatively, the compound of the formula XIII may be reacted with hexamethylene tetraamine and trifluoroacetic acid at a temperature from about 25xc2x0 C. to about 80xc2x0 C., preferably at about 70 xc2x0 C., to yield the same product.
preferably at about 70xc2x0 C., to yield the same product.
Scheme 3 illustrates a preferred method of preparing compounds of the formula X wherein G is hydrogen and R1 is a nitrogen containing heterocyclic group (e.g., a pyrrolyl, triazolyl or imidazolyl group). Referring to scheme 3, the xe2x80x94CHO group of a benzaldehyde of the formula XIV is protected by conversion to the corresponding 1,3-dioxolane of formula XV, wherein R5 is a suitable leaving group such as iodine or bromine, This reaction is generally carried out by heating a mixture of the benzaldehyde and ethylene glycole in an inert solvent such as benzene or toluene, preferably in the presence of an acid catalyst such as p-toluenesulfonic acid, and preferably at the reflux temperature of the solvent to remove the water formed in the reaction.
The resulting compound of formula XV is then reacted with a heterocyclic compound of the formula R1H to form the corresponding compound of formula XVI. Typically, the reaction is carried out in an aprotic, nonpolar solvent such as xylene or toluene, or in the absence of a solvent (e.g., as a melt of imidazole and the compound of the formula XV) at a temperature from about 100xc2x0 C. to about 300xc2x0 C., in the presence of an inorganic metal catalyst such as copper metal or copper iodide, in a high pressure reactor at a pressure from about 1 atm to about 5 atm. Preferably, the reaction is carried out neat using a copper metal catalyst, at a temperature from about 140xc2x0 C. to about 160xc2x0 C. and at a pressure from about 2 atm to about 3 atm.
Treatment of the compound of formula XVI formed in the above reaction with a mixture of aqueous hydrochloric acid in acetone at a temperature from about 0xc2x0 C. to about 50xc2x0 C., preferably at room temperature, will convert the dioxolane to the desired compound of formula X.
Alternatively, compounds of the formula X wherein G is hydrogen and R1 does not contain an ionizable proton (for example, R1=2-pyridyl, 2-thienyl or 2-pyrimidinyl) can be prepared by reacting a compound of the formula XV, as depicted in scheme 3 and defined above, wherein R5 is bromine or iodine, with magnesium metal to form a Grignard reagent of the formula 
and then reacting the Grignard reagent in situ with a halogen substituted heterocyclic compound of the formula Xxe2x80x3R1 wherein Xxe2x80x3 is chloro, bromo or iodo under standard Grignard conditions. These reactions are typically conducted in an ethereal solvent (e.g., diethyl ether or tetrahydrofuran), at a temperature from about 0xc2x0 C. to about 70xc2x0 C. They are preferably conducted at the reflux temperature of the solvent in the presence of a catalyst (e.g., tetrakis (triphenylphosphine) palladium (0)).
Compounds of the formula X wherein G is other than hydrogen can be prepared from commercially available sources by methods well known to those skilled in the art. For example, compounds of the formula X wherein G is hydroxy can be obtained by: (1) oxidizing the corresponding compounds of the formula 
wherein R20 is methyl with potassium permanganate in a reaction inert solvent such as acetone; (2) oxidizing an alcohol of the formula XVII wherein R20 is hydroxymethyl with manganese dioxide; or (3) subjecting a compound of the formula XVII wherein R20 is chloro, bromo or iodo to Grignard reaction conditions (i.e., reacting the compound of formula XVII with magnesium metal to form an intermediate of the formula 
and then treating the intermediate with carbon dioxide.
The foregoing carboxylic acids of the formula X wherein G is hydroxy can be converted into the corresponding compounds of the formula X wherein G is chlorine or bromine by reaction with such reagents as sulfonyl chloride, phosphorus trichloride, phosphorus pentachloride and phosphorous tribromide.
Carboxylic esters of the formula X wherein G is (C1-C6) alkoxy can be prepared by a variety of methods known in the art. One such method involves reacting the corresponding acid halide in a (C1-C6) alkanol in the presence of a catalytic amount of hydrochloric, sulfuric or para-toluenesulfonic acid at a temperature from about room temperature to about the boiling point of the alcohol employed.
Compounds of the formula Ia wherein R1 is pyrrolyl can also be prepared from the corresponding compounds wherein R1 is replaced by an amino group. The corresponding amine may be obtained by reducing the corresponding nitro compound using one of several methods known to those skilled in the art. One such method involves catalytic hydrogenation of the nitro compound using hydrogen gas and a palladium on carbon catalyst in an inert solvent such as methanol or ethanol at about room temperature and a pressure of about 1-5 atm. The reduction can also be accomplished using a reducing agent such as borane/methyl sulfide in tetrahydrofuran at a temperature from about 25xc2x0 C. to about 70xc2x0 C., preferably at the reflux temperature of the solvent. The latter reduction method is exemplified in Example 45 of U.S. patent application Ser. No. 07/932,392, filed on Aug. 19, 1992. This application is incorporated herein by reference in its entirety.
The amine can then be converted into the desired compound of formula I by the procedure described in Example 9.
Scheme 4 illustrates a method of preparing compounds of the formula 
wherein R22 is methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethy., (C1-C6) or benzyl, and R23 is methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, (C1-C6) alkyl, benzyl or phenyl optionally substituted with from one to three substituents independently selected from halo, trifluoromethoxy, (C1-C6) alkyl and (C1-C6) alkoxy. These aldehydes are intermediates in the synthesis of compounds of the formula Ib wherein W is OR22, Xxe2x80x2 is xe2x80x94Sxe2x80x94, Yxe2x80x2 is CR23 and Zxe2x80x2 is=Nxe2x88x92. Such compounds of the formula Ib may be prepared from the foregoing aldehydes of formula XVIII as described above and depicted in scheme 1.
Referring to scheme 4, compounds of the formula XX may be prepared by direct alkylation of the corresponding phenols of the formula XIX using a common alkylating agent such as dimethyl sulfate, a methyl halide (e.g., methyl iodide), methyl triflate, methyl mesylate or methyl tosylate. The reaction is usually conducted in an inert solvent such as dimethyl formamide, N-methyl pyrrolidinone, tetrahydrofuran, methylene chloride or another similar solvent for a period of about 0.5 to 12 hours at a temperature of about 0xc2x0 C. to the reflux temperature of the solvent. Typically, a base such as sodium hydride or potassium hydride is used, but other bases such as triethylamine, 1,8-diazobicyclo[5.4.0]undec-7-ene may be utilized as well. During the alkylation process, the carboxylic acid functionality of the phenol of formula XIX is also alkylated. However, various esterified derivatives of the compounds of formula XIX such as suitable starting materials for the foregoing transformation.
Reduction of the nitro functionality in the resulting compound of formula XX to yield the corresponding amine of formula XXI may be effected through hydrogenation with a noble metal catalyst such as platinum or palladium under a pressure of about 1-14 100 atmospheres of hydrogen gas in an inert solvent such as methanol, ethanol, ether, tetrahydrofuran or water (or a mixture of two or more such solvents). The reaction is most conveniently run at ambient temperature for about 0.5 to 12 hours. Alternatively, reduction of the nitro functionality may be carried out using a metal such as zinc or tin in a solvent such as acetic acid or water.
Formation of the amide of formula XXII is most conveniently conducted in an inert solvent such as methylene chloride, dichloroethane, tetrahydrofuran or toluene using one or more equivalents of an acylating agent such as acetic anhydride, acetyl chloride, benzoyl chloride, trimethylacetyl chloride, cyclopropyl carbonyl chloride or another alkyl or aryl acid chloride or anhydride. The reaction is most conveniently carried out in the presence of a base such as triethylamine or diisopropylamine or in aqueous solution under Schotten-Baumann conditions with sodium hydroxide. The reaction is generally conducted between about 0xc2x0 C. and 60xc2x0 C., with room temperature being preferred.
The thioamide of formula XXIII is formed from the corresponding amide of formula XXII by reacting the latter compound with a reagent such as 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson""s Reagent) or phosphorous pentasulfide in an inert solvent such as toluene, benzene, dichloroethane, dimethylformamide or hexamethylphosphorous triamide at a temperature from about room temperature to the reflux point of the solvent. The reaction may alternatively be run neat (without a solvent).
Cyclization of the thioamide of formula XXIII to form a mixture of regioisomeric benzothiazoles of the formulae XXIV and XXV is carried out by reacting the substrate with potassium ferricyanide in an aqueous base heated to about 50xc2x0 C. for a period of about 1 to 12 hours. The mixture of regioisomers may be separated at this point or carried through to the end of the synthetic sequence.
Reduction of the mixture of compounds of the formulae XXIV and XXV or of the compound of formula XXIV alone can be conducted using a reducing agent such as lithium aluminum hydride, borane-THF, sodium bismethoxyethylaluminum hydride or a similar reducing agent in an inert solvent such as ether, tetrahydrofuran, dimethoxyethane or toluene. The reaction may be carried out at a temperature between about 0xc2x0 C. and room temperature for a period of about 1 to 12 hours.
The resulting mixture of the regioisomeric alcohols of the formulae XXVI and XXVII (or XXVI separately) may be oxidized to form the desired aldehyde of formula XXVIII by reacting it with manganese dioxide in refluxing methylisobutyl ketone or another inert solvent for a period of about 1-14 12 hours. Alternatively, the oxidation can be carried out under xe2x80x9cSwernxe2x80x9d conditions (i.e., a mixture of dimethyl sulfoxide in methylene chloride with activation by oxalyl chloride or trifluoroacetic anhydride) or using other methods well known to those familiar with the art. Also effective are oxidizing agents such as pyridinium chlorochromate and pyridinium dichromate in an inert solvent such as methylene chloride, chloroform or dichloroethane.
The preparation of other compounds of the formula I not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
In each of the reactions discussed or illustrated in schemes 1 to 4 above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally acceptable, and ambient pressure, i.e. about 1 atmosphere, is preferred as a matter of convenience.
The novel compounds of the formula I and the pharmaceutically acceptable salts thereof are useful as substance P antagonists, i.e., they possess the ability to antagonize the effects of substance P as its receptor site in mammals, and therefore they are able to function as therapeutic agents in the treatment of the aforementioned disorders and diseases in an afflicted mammal.
The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the Formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
Those compounds of the formula I which are also acidic in nature, e.g., where R6 or R10 is carboxyphenyl, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
The compounds of formula I and their pharmaceutically acceptable salts exhibit substance P receptor-binding activity and therefore are of value in the treatment and prevention of a wide variety of clinical conditions the treatment or prevention of which are effected or facilitated by a decrease in substance P mediated neurotransmission. Such conditions include inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, urinary incontinence, gastrointestinal disorders such as emesis and colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud""s disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer""s disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis. Hence, these compounds are readily adapted to therapeutic use as substance P antagonists for the control and/or treatment of any of the aforesaid clinical conditions in mammals, including humans.
The compounds of the formula I and the pharmaceutically acceptable salts thereof can be administered via either the oral, parenteral or topical routes. In general, these compounds are most desirably administered in dosages ranging from about 5.0 mg up to about 1500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.07 mg to about 21 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
The compounds of the formula I and their pharmaceutically acceptable salts (xe2x80x9cthe therapeutic compoundsxe2x80x9d) may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the three routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutic compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
Additionally, it also possible to administer the therapeutic compounds of the present invention topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The activity of the therapeutic compounds of the present invention as substance P receptor antagonists may be determined by their ability to inhibit the binding of substance P at its receptor sites in bovine caudate tissue, employing radioactive ligands to visualize the tachykinin receptors by means of autoradiography. The substance P antagonizing activity of the herein described compounds may be evaluated by using the standard assay procedure described by M. A. Cascieri et al., as reported in the Journal of Biological Chemistry, Vol. 258, p. 5158 (1983). This method essentially involves determining the concentration of the individual compound required to reduce by 50% the amount of radiolabelled substance P ligands at their receptor sites in said isolated cow tissues, thereby affording characteristic IC50 values for each compound tested.
In this procedure, bovine caudate tissue is removed from a xe2x88x9270xc2x0 C. freezer and homogenized in 50 volumes (w./v.) of an ice-cold 50 mM Tris (i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol) hydrochloride buffer having a pH of 7.7. The homogenate is centrifuged at 30,000xc3x97G for a period of 20 minutes. The pellet is resuspended in 50 volumes of Tris buffer, rehomogenized and then recentrifuged at 30,000xc3x97G for another twenty-minute period. The pellet is then resuspended in 40 volumes of ice-cold 50 mM Tris buffer (pH 7.7) containing 2 mM of calcium chloride, 2 mM of magnesium chloride, 4 xcexcg/ml of bacitracin, 4 xcexcg/ml of leupeptin, 2 xcexcg of chymostatin and 200 g/ml of bovine serum albumin. This step completes the production of the tissue preparation.
The radioligand binding procedure is then carried out in the following manner, viz., by initiating the reaction via the addition of 100 xcexcl of the test compound made up to a concentration of 1 xcexcM, followed by the addition of 100 xcexcl of radioactive ligand made up to a final concentration 0.5 mM and then finally by the addition of 800 xcexcl of the tissue preparation produced as described above. The final volume is thus 1.0 ml, and the reaction mixture is next vortexed and incubated at room temperature (ca. 20xc2x0 C.) for a period of 20 minutes. The tubes are then filtered using a cell harvester, and the glass fiber filters (Whatman GF/B) are washed four times with 50 mM of Tris buffer (pH 7.7), with the filters having previously been presoaked for a period of two hours prior to the filtering procedure. Radioactivity is then determined in a Beta counter at 53% counting efficiency, and the IC50 values are calculated by using standard statistical methods.
The ability of the therapeutic compounds of this invention to inhibit substance P induced effects in vivo may be determined by the following procedures xe2x80x9caxe2x80x9d through xe2x80x9cdxe2x80x9d. (Procedures xe2x80x9caxe2x80x9d through xe2x80x9ccxe2x80x9d are described in Nagahisa et al., European Journal of Pharmacology, 217, 191-5 (1992), which is incorporated herein by reference in its entirety.
a. Plasma extravasation in the skin
Plasma extravasation is induced by intradermal administration of substance P (50 xcexcl, 0.01% BSA-saline solution) in dorsal skin of pentobarbital (25 mg/kg i.p.) anesthetized male Hartley guinea pigs weighing 450-500 g. The compound to be tested is dissolved in 0.1% methyl cellulose-water (MC) and dosed p.o. 1 hour before substance P challenge (3 pmol/site). Evans blue dye (30 mg/kg) is administered intravenously 5 minutes before challenge. After 10 minutes, the animals are sacrificed, the dorsal skin is removed, and the blue spots are punched out using a cork borer (11.5 mm oral dose o.d.)). Tissue dye content is quantitated after overnight formamide extraction at 600 nm absorbance.
b. Capsaicin-induced plasma extravasation
Plasma extravasation is induced by intraperitoneal injection of capsaicin (10 ml of 30 xcexcM solution in 0.1% BSA/saline) into pentobarbital anesthetized (25 mg/kg i.p.) guinea pigs. The compound to be tested is dissolved in 0.1% MC and dosed p.o. 1 hour before capsaicin challenge. Evans blue dye (30 mg/kg) is administered i.v. 5 minutes before challenge. After 10 minutes, the animals are sacrificed, and both right and left ureters are removed. Tissue dye content is quantitated as in xe2x80x9caxe2x80x9d above.
c. Acetic acid-induced abdominal stretching
Male ddY mice (SLC, Japan), weighing 14-18 g, were fasted overnight. The compound to be tested is dissolved in 0.1% MC and dosed p.o. 0.5 hour before acetic acid (AA) injection (0.7%, 0.16 ml/10 g body weight). The animals are placed in clear beakers (1 per beaker) and the stretching response is counted 10 to 20 minutes after the AA injection (10 minute interval).
d. Substance P-induced hyperlocomotor paradigm
The anti-psychotic activity of the therapeutic compounds of the present invention as neuroleptic agents for the control of various psychotic disorders may be determined by a study of their ability to suppress substance P-induced or substance P agonist induced hypermotility in guinea pigs. This study is carried out by first dosing the guinea pigs with a control compound or with an appropriate test compound of the present invention, then injecting the guinea pigs with substance P or a substance P agonist by intracerebral administration via canula and thereafter measuring their individual locomotor response to said stimulus.
The present invention is illustrated by the following examples. It will be understood, however, that the invention is not limited to the specific details of these examples.
A mixture of 0.99 grams (5.15 mmol) of 4-(4-methoxyphenyl)-1,2,3-thiadiazole (Maybridge Chemical Co.) in 23 mL of anhydrous methylene chloride (Ch2Cl2) cooled to 0xc2x0 C., was treated with 2.3 mL (21.9 mmol) of titanium tetrachloride and stirred for 30 min. The red solution was treated with 0.97 mL (10.7 mmol) of xcex1,xcex1-dichloromethyl methyl ether and allowed to warm to room temperature overnight. The reaction mixture was then poured over 100 mL of saturated aqueous sodium bicarbonate (NaHCO3), the pH was adjusted to 7-8 with solid NaHCO3 and the solution was then extracted with CH2Cl2. The organic layer was dried with magnesium sulfate (MgSO4) and concentrated to a yellow solid. Chromatography on silica gel (20% EtOAc: 80% Hexane) gave the pure title compound as a light yellow solid, 0.35 g (31%).
M.P. 156-157xc2x0 C.
1H NMR (DMSO-d6) xcex4 4.0 (s, 3H), 7.4 (d, 1H), 8.4 (m, 2H), 9.7 (s, 1H), 10.4 (s, 1H).
In the same manner, the following aldehyde intermediates were prepared:
M.P. 119-120xc2x0 C.
1H NMR (CDCl3) xcex4 4.0 (s, 3H), 7.1 (d, 1H), 7.3 (d, 1H), 7.8 (d, 1H), 8.2 (dd, 1H), 8.3 (d, 1H), 10.5 (s, 1H).
1H NMR (CDCl3) xcex4 2.46 (s, 3H), 3.95 (s, 3H), 6.82 (s, 1H), 7.02 (d, J=8.7 Hz, 1H), 8.15 (dd, 1H), 8.26 (d, J=2.4 Hz, 1H), 10.46 (s, 1H).
1H NMR (CDCl3) xcex4 4.0 (s, 3H), 7.1 (d, 1H), 7.4 (s, 1H), 7.8 (dd, 1H), 7.9 (s, 1H), 8.1 (d, 1H), 10.5 (s, 1H).
1H NMR (CDCl3, free base) xcex4 2.6 (s, 3H), 3.95 (s, 3H), 7.0 (m, 2H), 7.4 (d, 1H), 7.6 (d, 1H), 8.3 (dd, 1H), 8.5 (d, 1H), 10.5 (s, 1H).
Mass Spectrum (m/e, %): 228 (M+1), 227 (m+, 40), 85 (100).
1H NMR (CDCl3, free base) xcex4 4.0 (s, 3H), 7.1 (d, 1H), 7.2 (q, 1H), 7.7 (d, 2H), 8.3 (dd, 1H), 8.4 (d, 1H), 8.7 (d, 1H), 10.5 (s, 1H).
M.p. 77-79xc2x0 C.
1H NMR (CDCl3, free base) xcex4 4.0 (s, 3H), 7.2 (d, 1H), 7.4 (m, 1H), 7.8 (dd, 1H), 7.9 (dd, 1H), 8.1 (d, 1H), 8.6 (dd, 1H), 8.9 (d, 1H), 10.5 (s, 1H).
1H NMR (CDCl3, free base) xcex4 4.0 (s, 3H), 7.1 (d, 1H), 7.2 (t, 1H), 8.7 (d, 1H), 8.8 (d, 2H), 9.0 (d, 1H), 10.5 (s, 1H).
Mass Spectrum (m/e, %): 215 (M+1, 100), 214 (M+, 35).
1H NMR (CDCl3, free base) xcex4 2.4 (s, 6H), 4.0 (s, 3H), 6.0 (s, 1H), 7.05 (d, 1H), 7.6 (dd, 1H), 7.85 (d, 1H), 10.5 (s, 1H).
Mass Spectrum (m/e, %): 231 (M+1, 100).
M.p. 115-117xc2x0 C.
1H NMR (CDCl3, free base) xcex4 1.9 (s, 3H), 2.1 (d, 6H), 4.0 (s, 3H), 7.0 (d, 1H), 7.8 (m, 1H), 7.9 (d, 1H), 10.5 (s, 1H).
Mass Spectrum (m/e, %): 245 (M+1, 100).
1H NMR (CDCl3, free base) xcex4 1.4 (d, 6H), 2.0 (s, 3H), 2.17 (s, 3H), 2.2 (s, 3H), 4.70 (m, 1H), 7.05 (d, 1H), 7.6 (dd, 1H), 7.8 (d, 1H), 10.5 (s, 1H).
1H NMR (CDCl3, free base) xcex4 1.2 (d, 6H), 1.3 (d, 6H), 3.0 (m, 2H), 4.0 (s, 3H), 6.1 (s, 1H), 7.0 (d, 1H), 7.6 (dd, 1H), 7.9 (d, 1H), 10.5 (s, 1H).
Mass Spectrum (m/e, %): 286 (m+, 75), 271 (100).
1H NMR (CDCl3, free base) xcex4 2.25 (s, 3H), 2.5 (s, 3H), 3.9 (s, 3H), 6.9 (d, 1H), 7.15 (d, 1H), 7.25 (m, 2H), 9.8 (s, 1H).
Mass Spectrum (m/e, %): 246 (M+, 100), 231 (35).
M.p. 155-160xc2x0.
1H NMR (CDCl3, free base) xcex4 2.2 (s, 3H), 2.45 (s, 3H), 4.0 (s, 3H), 7.0 (d, 1H), 7.8 (d, 1H), 10.7 (s, 1H).
Mass Spectrum (m/e, %): 221 (M+1, 100).
6-Methoxy-2-methyl-benzoxazole (1.06 grams, 6.5 mmol) was taken up in 65 mL of dry methylene chloride and cooled to 0xc2x0 C. Titanium tetrachloride (10.11 grams, 53.3 mmol) was added via syringe and the deep red solution was stirred for 30 min. Dichloromethyl methyl ether (4.63 grams, 40.3 mmol) was added dropwise and the reaction mixture darkened to a brown color. The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. The mixture was quenched into ice and water. The slurry was basified with aqueous saturated bicarbonate and extracted with methylene chloride. The organic phase was washed with saturated aqueous brine and then dried and evaporated in vacuo. The residue was chromatographed on silica eluting over a gradient of 20% ethyl acetate/hexanes to 50% ethyl acetate/hexanes. In addition to starting material, a more polar material, the desire aldehyde, was obtained in 69 mg. Further elutions led to the isolation of a regioisomeric aldehyde. The desired material displayed the following spectral data.
1H NMR (250 MHz, CDCl3) xcex4 10.48 (s, 1H), 8.10 (s, 1H), 7.06 (s, 1H), 3.98 (s, 3H), 2.62 (s, 3H).
6-Methoxy-2-methyl benzothiazole [3.34 grams (18.63 mmol)] was taken up in 35 mL of trifluoroacetic acid and treated with 2.62 grams (18.63 mmol) of hexamethylenetetramine. The reaction was heated under reflux for seven hours. The reaction mixture was allowed to cool and was evaporated in vacuo. The residue was diluted with 200 mL of ethyl acetate and treated with 100 mL of saturated sodium bicarbonate solution. The organic phase was washed with saturated brine solution and was dried and evaporated. The residue was chromatographed on silica gel (elution with 20% ethyl acetate in hexanes) to provide 3.04 grams of recovered starting material and 10 mg of the desired aldehyde.
1H NMR (250 MHz, CDCl3) xcex4 10.52 (s, 1H), 8.36 (s, 1H), 7.38 (s, 1H), 3.99 (s, 3H), 2.82 (s, 3H).
In a similar manner, the following aldehyde intermediate was prepared.
6-Methoxy-3-methyl-benzo[d]isoxazole (1.4 g, 8.58 mmol) was taken up in 200 mL of trifluoroacetic acid and treated with 1.20 grams (8.6 mmol) of hexamethylenetetramine. The reaction was heated under reflux for 24 hours. The reaction mixture was allowed to cool and was evaporated in vacuo. The residue was diluted with 200 mL of methylene chloride and treated with 200 mL of saturated sodium bicarbonate solution. The organic phase was washed with saturated brine solution and was dried and evaporated. The residue was chromatographed on silica gel (elution with 15% ethyl acetate in hexanes) to provide 122.6 mg of the desired aldehyde.
1H NMR (250 MHz, CDCl3) xcex4 10.46 (s, 1H), 8.15 (s, 1H), 7.04 (s, 1H), 4.02 (s, 3H), 2.56 (s, 3H).
To a solution of 2.04 grams (8.72 mmol) of 4-iodoanisole in 36 mL of CH2Cl2, cooled to 0xc2x0 C., was added dropwise 2.0 mL (18.7 mmol) of titanium tetrachloride. After stirring for 30 min., 0.93 mL (10.3 mmol) of xcex1, xcex1-dichloromethyl methyl ether was added and the reaction maintained at 0xc2x0 C. for another 2 hours. The reaction mixture was then poured with stirring into a mixture of 50 mL of CH2Cl2 and 50 mL of saturated aqueous sodium bicarbonate (NaHCO3). After 30 min., this was filtered through diatomaceous earth, the organic layer was separated, the aqueous layer was twice extracted with CH2Cl2, and all of the organic layers were combined, dried with MgSO4 and concentrated in vacuo. The crude residue was recrystallized from ethanol (EtOH) to give 5-iodo-2-methoxybenzaldehyde as pale yellow needles, 1.37 grams (60%).
1H NMR (CDCl3) xcex4 4.0 (s, 3H), 6.8 (d, 1H), 7.8 (dd, 1H), 8.1 (d, 1H), 10.4 (s, 1H).
A solution of 1.0 grams (3.82 mmol) of the above aldehyde, 0.85 mL of ethylene glycol, 20 mg of p-toluenesulfonic acid and 42 mL of toluene was refluxed under nitrogen for 18 hours, cooled and concentrated in vacuo. The residue was redissolved in 50 mL of CH2Cl2, washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated to an oil. Chromatography on silica gel (10% ethyl acetate (EtOAc): 90% hexane) gave 2-(5-iodo-2-methoxyphenyl)-1,3-dioxolane as a clear oil, 0.68 grams (58%).
1H NMR (CDCl3) xcex4 3.9 (s, 3H), 4.0-4.3 (m, 4H), 6.1 (s, 1H), 6.7 (d, 1H), 7.4 (dd, 1H), 7.9 (d, 1H).
In a Pyrex high pressure reaction tube, a solution of the preceding dioxolane (200 mg, 0.66 mmol), 140 mg (2.06 mmol) of imidazole and 90 mg (1.4 mmol) of copper powder in 1 mL of anhydrous tetrahydrofuran (THF) was stirred until homogeneous. The solvent was then evaporated under nitrogen, and the tube was sealed and heated in an oil bath at 140xc2x0 C. for 16 hours. After cooling, the residue was dissolved in 20 mL of THF, filtered through a pad of diatomaceous earth and concentrated in vacuo to an oil. Chromatography on silica gel (100% ethyl acetate (EtOAc)) gave 60 mg of 2-(5-(2-imidazolyl)-2-methoxyphenyl)-1,3-dioxolane as a yellow oil.
MS: m/e 246 (m+).
The preceding oil in 20 mL of acetone was treated with 10 mL of 1 N hydrochloric acid (HCl) and stirred at 25xc2x0 C. for 3 hours, evaporated in vacuo and extracted into CH2Cl2. After washing with water, the organic layer was dried over MgSO4 and concentrated to a clear oil. Chromatography on silica gel (3% CH3OH: 97% CH2Cl2) gave 5-(2-imidazolyl)-2-methoxybenzaldehyde as a clear oil, 30 mg (61%).
1H NMR (CDCl3) xcex4 4.0 (s, 3H), 7.1 (d, 1H), 7.1-7.3 (m, 2H), 7.6 (dd, 1H), 7.8 (d, 2H), 10.5 (s, 1H).